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Infectious Diseases
Amelia Co-Fibra MD, FPSP
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UNDERSTANDING PATHOGENESES OF INFECTIOUS AGENTS
1. Enumerate the categories of Infectious agents and their general features
2. Know the different human barriers against infectious agents
3. To enumerate and understand the Transmission & Dissemination of microbes
4. To know how microbes cause disease A. VIRAL INJURY B. BACTERIAL INJURY C. INJURIOUS EFFECTS OF HOST IMMUNITY
COURSE OUTLINE
KNOW DISEASES PRODUCED BY SOME OF THE INFECTIOUS AGENTS◦A. VIRAL INFECTION◦B. BACTERIAL INFECTION◦C. PARASITES◦D. FUNGAL
COURSE OUTLINE
PRIONS VIRUSES BACTERIOPHAGES/ PLASMIDS/ TRANSPOSON BACTERIA CHLAMYDIA / RICKETTSIAE/ MYCOPLASMA FUNGI PROTOZOA HELMINTHS ECTOPARASITES
Categories of Infectious Agents
Classes of Human PathogensTaxonomic Site of Propagation Examples Diseases
Prions Intracellular Prion protein Creutzfeld- Jacob Disease
Viruses Obligate Intracellular Poliovirus Poliomyelitis
Bacteria 1. Obligate Intracellular2. Extracellular3. Facultative intracellular
1. Chlamydia trachomatis2. Strep pneumoniae3. TB
TrachomaPneumoniaTuberculosis
Fungi 1. Extracellular2. Facultative intracellular
1. Candida albicans2. Histoplasma
capsulatum
ThrushHistoplasmosis
Protozoa 1. Extracellular
2. Facultative intracellular3. Obligate intracellular
1. Trypanosoma gambiense
2. T. cruzi3. Leishmania donovani
1. Sleeping sickness
2. Chagas dse3. Kala- azar
Helminths 1. Extracellular2. Intracellular
1. Wuchereria bancrofti2. Trichinella spiralis
1. Filariasis2. Trichinosis
PRIONS
Nucleic acid freeSpontaneous mutation or Inherited Mutation in PrP
Cause Transmissible Spongiform Encephalitis
PathophysiologyPrP found in neurons
Mutation• Conformational change
Abnormal PrP• Resistant to PROTEASES
Neuronal damage
Abnormal PrP promotes transformation of normal PrP to abnormal formsEXPLAINING THE INFECTIOUS NATURE OF THESE DISEASE
Cause Transmissible Spongiform encephalitis◦ Kuru ( Human Cannibalism )◦ Bovine Spongiform Encephalitis ( Mad Cow
Disease )◦ Creutzfeldt-Jacob Disease
(Spontaneous - Sporadic/ Inherited -Familial) Transmitted
From corneal/ organ transplant BSE infected cattle Blood Transfusion
Vacuolization of gray matter but no inflammation
Clinical presentation
Obligate Intracellular 20-300nm May aggregate forming inclusion bodies
◦ CMV – large eosinophilic inclusion Nucleic acid core surrounded by capsid Cause
◦ Transient illness ( colds, influenza)◦ Not eliminated persist w/in cells
Continue to multiply ( HEPATITIS B ) Non-replicating OR Latent ( chickenpox shingles)
◦ May transform host cell tumor / cancer cell( Human papilloma virus )
VIRUSES
Mobile genetic elements that infect bacteria
Indirectly cause human diseases◦ Encodes virulence factor◦ Exchange of these elements between bacteria
Bacteriophages/ plasmids◦ Converts Nonpathogens Pathogens
Plasmids/ Transposons◦ Encode antibiotic resistance◦ Eg. Vancomycin – resistant enterococci
BACTERIOPHAGE, PLASMIDS, TRANSPOSONS
Prokaryotes – have cell membrane◦Gram positive - thick wall surrounding the
cell membrane (stain violet )◦Gram negative - thin cell wall sandwich
between 2 phospholipid bilayer membranes ( stain red )
Lack Nuclei Most synthesize their own DNA/RNA Depend on host for Favorable Environment
◦Intracellular or Extracellular
Bacteria
Divide by binary fusion Mycoplasma
◦ Lack cell wall ◦ Mycoplasma are tiniest living organism◦ Airborne transmission◦ Binds surface epithelial cells in airway
Chlamydia ◦ Lack metabolic capabilities (ATP)
Chlamydia & Rickettsia Obligate intracellular organism◦ Mulitply in vacuoles inside the cell
CHLAMYDIA, RICKETTSIAE, MYCOPLASMA
FUNGI PROTOZOA
Eukaryotes – thick chitin walls & ergosterol membrane
Most exhibit Thermal Dimorphism
HEALTHY PERSONS◦ Dermatophytes – skin◦ Subcutaneous tissue abscess &
granulomas IMMUNOCOMPROMISED
◦ Deep fungal infxn invade tissues
AIDS◦ Lethal Pneumonia by
Opportunistic Pneumocystis carinii
Single-celled eukaryotes
Trichomonas vaginalis Intestinal protozoa Blood borne protozoa
◦ Plasmodium spp
HELMINTHS ECTOPARASITES
Multicellular organism Life cycle Roundworms-
Nematodes◦ ASCARIS◦ FILARIA/ TRICHINELLA
Flatworms- Cestodes◦ Tapeworms
Flukes – Trematode◦ Schistosoma
Arthropods◦ Lice◦ Ticks◦ Bedbugs
Live on the skin May be vectors for
other pathogens◦ Lyme disease by ticks
TRANSMISSION & DISSEMINATION OF MICROBES
A. ROUTES OF ENTRY B. SPREAD & DISSEMINATIONC. RELEASE OF MICROBESD. SEXUALLY TRANSMITTED INFECTION
HOST BARRIERS TO INFECTION & ROUTES
OF ENTRY
SKIN
Barrier – inhibit growth of microbes except normal flora
Pathogens
1. KERATINIZED SKIN2. LOW SKIN pH 5.53. FATTY ACID
1. DERMATOPHYTES infect stratum corneum
2. SCHISTOSOMA LARVAE penetrate the skin- enzyme collagenase dissolve matrix
3. INSECT/ANIMAL BITES4. NEEDLE STICKS5. BREAK in the skin
1. Acidic gastric pH2. Viscous mucous3. Lytic pancreatic enzymes/ bile4. Mucosal antimicrobial peptides -
Defensin5. Normal flora6. Secreted IgA- produced by plama cells in
MALT ( M cells ) transport of antigens to
MALT and for binding/uptake of gut pathogens
GIT- Barrier
Local Defenses Weaken Low gastric acidity Antibiotics Stalled peristalsis
Organism develop strategies to overcome defenses Nonenveloped viruses may resist digestive
enzymes - HAV, Rotavirus Cyst form – Protozoans
GIT-Infection
Barriers Pathogens1. Mucociliary Blanket in
Upper airway2. Mucus from goblet –
Large particles3. Alveolar
macrophages/pmns – Smaller particles < 5 um
1. Impair cilia activity 2. Escape macrophages
(TB)3. Immunosuppression Elaborate Toxins- Hemophilus,
BordetellaChronic SmokersAspiration of Gastric contents
RESPIRATORY
Respiratory Pathogens Influenza Virus
◦ (+) Hemagglutinin proteins on surface bind sialic acid on epithelium of host engulf by cell virus replicate inside cell
◦ (+) Neuramidase Cleaves sialic acid – Allow viral release from cell Lowers the viscosity of the mucus facilitates viral
transit
Staphyloccoci ( Secondary Infection )◦ Gain access to host cell after viral infxn cause
loss of ciliated epithelium
BARRIERS PATHOGEN
1. Regular flushing of urinary tract
2. Vagina is protected by Low pH – breakdown of Glycogen in epithelium by Lactobacilli
Pathogens invade-Short urethra in females-Obstruction/ Reflux
-STD Develop mechanism for attaching to vagina/ cervix-Enter breaks in mucosa
UROGENITAL
Spread & Dissemination of
Microbes
1. Proliferate Locally at the site◦Adhere & Proliferate in/on Epithelial Cells
HPV , Dematophytes◦Confined to Lumen of Hallow Viscera
Cholera
Spread & Dissemination of Microbes
2. Penetrate the epithelial barrier Spread via Hematogenous or Lymphatic or Nerve◦ Invasiveness Due to:
Motility Secrete Lytic enzymes- Hyaluronidase
Degrades extracellular matrix between cells Strep & Staph
◦ Initial spread Follow tissue Planes of Least Resistance Regional LN Blood Stream Distant organs Abscess Regional LNs Bacteremia Colonize
distant organs
Spread & Dissemination of Microbes
Spread & Dissemination of Microbes
HEMATOGENOUS SPREADFREE - Polio, HBV, fungi, protozoa W/in WBC – HSV, HIV, TBW/in RBC - Plasmodium
Nerve
3. Viral Propagation◦ A). Propagate from Cell to Cell by replication◦ B). Propagate By Fusion or Transport within
Nerves – Rabies, VZV 4. Placental – Fetal Route
◦ Bacterial / Mycoplasma Placentitis Premature delivery
◦ Maldevelopment - Rubella Severe in Early trimester
◦ Syphilis affect mother late in 2nd Trimester◦ Passage to birth canal- Gonococcal, Chlamydia◦ Maternal Milk – CMV, HBV, HTLV-1
Spread & Dissemination of Microbes
Maternal transmission ◦ HIV – Major cause of AIDS in children◦ HBV – Can later cause Chronic Hepatitis & Liver
Ca
Notes:
RELEASE OF MICROBES FROM THE
BODYImportant in the Transmission
Release of Microbes from the Body
Release depends on the Location1.Skin shedding2.Coughing3.Sneezing4.Voiding – urine/ feces5.Insect vector
Respiratory◦ Viruses & Bacteria ◦ Infectious only when lesions are open to AIRWAYS
Fecal-oral◦ Water-borne viruses
HAV, HEV, Polio, Rotaviruses Saliva
◦ EBV, CMV, Mumps Larval penetration
◦ Hookworms, Schistosomiasis
Transmission- Person to Person
Sexual / Prolonged Intimate or Mucosal Contact◦ Viruses - HPV, HSV, HBV, HIV◦ Bacteria – Syphilis, Gonorrhea, Chlamydia◦ Protozoan – Trichomonas ◦ Candida
Blood & Blood products/ Needle pricks, etc◦ HBV, HCV, HIV
Transmission- Person to Person
Direct Contact or Consumption of Animal products
Indirectly via an Invertebrate vectors◦ Insects, Ticks, Mites
Transmission – Animals to HumanZOONOTIC INFECTIONS
SEXUALLY TRANSMITTED
INFECTONS
Sexually Transmitted InfectionSTransmitted through Sexual Contact Chlamydia & Neisseria – Usually by sexual
intercourseShigella & Entamoeba – Occasionally
spread by sexHigh Risk Groups for STI1. Adolescent2. Men with Men3. Illegal drug user
Organism tend to be short lived outside the host
Usually dependent on Direct person to person spread
Initial site of infection – urethra, vagina, rectum, oropharynx
Most are Asymptomatic carriers
STI
STI increases the Risk for additional STI’s - CoinfectionRisk factors are the same for all STI’sBiologic interaction between them
Increase the spread of infxnGonococcal cervicitis local tissue damage
Increased chance of HIV infxn STI Vertical Spread
C. trachomatis – conjunctivitis Neonatal Herpes simplex –
visceral&CNS disease
Syphilis – miscarriage
HOST DEFENSES AGAINST INFECTIONS
VIRULENCE◦Ability of microbe to infect , colonize,
damage host tissues HOST RESISTANCE
◦Ability of host defense mechanisms to eradicate infection – Innate & Adaptive Immune Defenses
Outcome of Infection – Determined
INNATE DEFENCES◦ Physical Barriers◦ Macrophages◦ NK cells◦ Plasma Proteins – Complement , Cytokines, Acute
phase reactants Adaptive Immune response
◦ Are stimulated by exposure to microbes◦ Increase in magnitude, speed & effectiveness with
successive exposure◦ Mediated by T & B lymphocytes and their products
Immune Defenses
HOW MICROORGANISMS
CAUSE DISEASE1. DIRECT LY CAUSE CELL
DEATH2. TOXIN / ENZYME
RELEASE3. INDUCE CELLULAR
RESPONSES
MECHANISMS OF VIRAL INJURY
Predilection of virus to infect certain cells and not others.
Tropism Determined : ◦ HOST CELL RECEPTOR- MAJOR DETERMINANT◦ CELLULAR TRANSCRIPTION FACTORS
That Recognize Viral Enhancer & Promoter Sequences Allow Viral replication inside the cell
◦ ANATOMIC BARRIER◦ LOCAL TEMPERATURE◦ pH◦ HOST DEFENSE
Tissue Tropism
1. Binding to host cell surface proteins◦ Viruses possess specific cell-surface PROTEINS◦ Viruses may use Normal Cellular Receptors of Host◦ Host Proteases are Needed For Binding
Host Proteases Cleaves & Activates Influenza Hemagglutinin
2. Translocation into cytosol 3. Replication via virus specific enzymes
Viruses Enter Host
(+) Hemagglutinin proteins on surface bind sialic acid on epithelium of host engulf by cell virus replicate inside cell(+) Neuramidase – lowers the viscosity of the mucus facilitates viral transit
Direct Cytopathic effects
• Viral killing of one cell type cause the death of the other cells• A
trophy of the muscles
Antiviral Immune responses
• Immune system kill infected cells
Transformation of infected cells into benign of malignant tumor cells
Mechanism of Viral injury
Preventing synthesis of host macro-molecules : DNA, RNA, CHON
• Polio virus
Produce Degradative enzymes & Toxic proteins
• HSV
• HIV
Cytopathic Effects - Virus Kill Cell Directly
Inducing Host immune response to virus – infected cells ◦ Host (CTL) Lymphocytes attack virus-infected cells
FAS Ligand on CTL binds FAS receptor in liver cells Eg. Hepatitis B virus
Virus Damage Cell involved in Host Antimicrobial Defense Secondary Infections
Viral killing of one cell type cause the death of the other cells◦ Motor denervation atrophy of the muscles
Antiviral Immune responses
1. ABORTIVE2. LATENT3. PERSISTENT
Viral Infection can be:
BACTERIAL INJURY TO HOST TISSUES
1. Bacterial Virulence2. ADHERE TO HOST CELLS ENTRY 3. DELIVER TOXINS4. Virulence of Intracellular Bacteria
Bacterial Virulence
Virulence of Intracellular microbe
Bacterial Toxins
Mechanism of Bacterial Injury
Virulence genes Plasmids & Bacteriophage
◦ Mobile genetic elements ◦ Spread between bacteria◦ Encode virulence factors – Abtic resistance, toxins
Quorum sensing◦ Induce expression of virulence factor as their
concentration in tissues increases◦ Eg. Staph aureus - abscess
Biofilm formation◦ Live in viscous layer of extracellular material◦ Enhance adherance & Inaccesible◦ IV catheters, Artificial joints
Bacterial Virulence
AdhesinsStrep. Pyogenes
• Have a Broad range of Host cell specificty
• Bind host cell or extracellular matrix
Gram (-) PiliE. coli
N. gonorrhea
• Tip of pili determine binding specificity
• Binds Uroepithelial cell
Bacterial Adherence
•Contain protein F & Lipoteichoic acid – bind fibronectin on epith. cells & matrix• M protein prevents phagocytosis
Gram (+) Fibrillae covering- Strep.
pyogenes
Bacterial Adherence
Infect either◦Epithelial cells – Shigella, Invasive E. coli◦Macrophages – Mycobacteria◦Both – S. typhi
Escape immune system- TB Facilitate spread Interact w/ cell
◦ Inhibit host CHON synthesis – Shigella & E.coli
◦Blocks fusion of acidic lysosome to form phagosome – M.TB
Virulence of Facultative Intracellular Bacteria
Bacteria coated w/ antibodies or
Complement C3b opsonization
( Alternate pathway – M. TB )
M. TB binds CR3 complement Receptor
on Macrophages
Endocytosed into macrophage- Escape host
immune- Facilitate spread
Some Mechanisms of Bacterial Entry to Cell
Gram (-) use complex secretion system
Needle like structures
Pores inject proteins
Cause rearrangemen
t of host cytoskeleton
Facilitate entry• Eg. Listeria
monocytogenes
Some Mechanisms of Bacterial Entry to Cell
Inhibit host protein synthesis Replicate rapidly Lyze host cell w/in 6 hours
Blocks fusion of lysosome with phagosome allow bacteria to replicate unchecked w/in macrophages
Effect of Bacteria inside the cell
Endotoxins
• Component of Bacterial cell
Exotoxins
• Proteins secreted by bacteria
Bacterial Toxins
Lipopolysaccharides◦Large outer cell wall of gram negative
Response of Host◦Beneficial◦Detrimental
ENDOTOXINS
1. Induction of cytokines & chemoattractants
2. Increased expression of co-stimulatory molecules enhance T-cell activation
Lipopolysaccharide- Beneficial Effect Activates immune response
High Levels of LPS• DIC , ARDS, SEPTIC SHOCK via Induction of excessive levels of
cytokines• TNF, IL-1, IL-12
Lipopolysaccharide-Harmful Effect
1. ENZYME - Protease staph.◦Split epidermis from dermis
2. TOXINS – with A-B toxins A subunit – enzymatic activity
INACTIVATES HOST PROTEINS – Cholera/Diptheria
DEGRADES HOST PROTEINS - Botulinum B-subunit – binding receptor & delivers
A subunit to the cell
Exotoxin- Secreted proteins
3. Neurotoxins – Clostridium botulinum & tetani◦Inhibit release of neurotransmitters◦But do not kill neurons
4. Superantigens – staph aureus, strep pyogenes◦Stimulate very large T-lymphos Lead to very high lymphocyte proliferation and cytokine release Capillary leak shock
Exotoxin
INJURIOUS EFFECTS OF HOST IMMUNITY
TB Granulomatous inflammation ( Delayed Hypersensitivity Reaction )◦ Prevents spread of microbe◦ But cause tissue Damage & Fibrosis
HepaB Immune response Liver damage Beta hemolytic Strep
◦ Ab against M protein Cross react w/ cardiac proteins RHD
◦ Ag + ASO (anti streptococcal antibodies) Deposit in renal glomeruli causing Poststreptococcal Glomerulonephritis
Immune response Tissue injury
IMMUNE EVASION BY MICROBES
A. Remaining inaccessible to host immune response
B. Varying or shedding antigensC. Resisting innate immune defensesD. Preventing T-cell activation E. Impairing effective T-cell
antimicrobial responses by specific or non-specific immunosuppression
Mechanism of Immune evasion by Microbes
Propagate in the lumen of ◦ Intestine – Clostridium difficile◦ Gallbladder – Salmonella typi
Shed from luminal surface of epithelial cells◦ CMV- urine, milk◦ Polio – stool
Infect the keratinized skin – Pox virus Infect Host cell – malaria Encyst in tissues – tapeworms Viral Latency – many viral genes are not
expressed
Inaccessible to Host Immune
Low fidelity of Viral RNA polymerases◦HIV
Reassortment of viral genomes◦Influenza virus
Different capsular polysaccharides◦Strep Pneumoniae
Shed antigens w/in minutes of penetrating the skin Preventing recognition by antibodies ◦ Schistosoma mansoni
Varying antigens / Shedding antigens
CAMP Resistance◦ Cationic antimicrobial peptides ( CAMP )
Defensin, Cathelicidins Initial defense against invading microbes
◦ Enabling them to avoid killing by pmns & macropahges
Carbohydrate Capsule◦ Pneumococcus, Meningococcus, Hemophilus
PREVENTI PHAGOCYTOSIS◦ K1 capsule containing sialic acid
E. coli- meningitis Sialic acid will not bind C3b ( alternate
complement pathway)
Resisting Innate Immune Response
Covering them with host proteins◦ Staph aureus covered by A molecules that
bind Fc portion inhibit Phagocytosis Protease
◦ Degrade antibodies ◦ Neisseria, Hemophilus, Streptococcus
Replicating w/in phagocytic cells◦ Mycobacterium, cryptococcus
Resisting Innate Immune Response
Some viruses block complement activation◦HERPESVIRUSES, POXVIRUS
Produce homologues of IFN/ IFN receptors ◦INHIBIT THE ACTION OF SECRETED IFN
Produce cytokine mimics◦EBV – homologue of IL 10
( Bind & Inhibit secreted IFN )
Resisting Innate Immune Response
Several DNA viruses Bind or Alter Localization of MHC class I proteinsHSV, EBV , CMV
Impairing peptide presentation to CD8 cytotoxic T cell
Decrease Recognition of Infected cells by CD4 , CD8
Express MCH class I homologues - Herpes Virus
Act as Inhibitors of NK cells • B
y engaging Killer Inhibitory receptors
Decrease Recognition of Infected cells
Herpes viruses Target MHC class II molecules for
Degradation & Impairing antigen presentation to CD4 + T helper cells
Decrease Recognition of Infected cells
Infected Lymphocytes Directly compromise
their functionHIV infect & Kill CD4 (+)T
lymphocytes, Macrophages, Dendritic
cells
EBV – infect B lymphocytes
Immunosuppression